RATIONALE: Radiation therapy uses high-energy x-rays and to kill tumor cells. Drugs used in chemotherapy, such as docetaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving radiation therapy together with chemotherapy is more effective with or without cetuximab in treating patients with esophageal cancer.

PURPOSE: This randomized phase III trial is studying giving radiation therapy together with chemotherapy, with or without cetuximab, followed by surgery in treating patients with locally advanced esophageal cancer that can be removed by surgery.

Further study details as provided by Swiss Group for Clinical Cancer Research:

Primary Outcome Measures:

Progression-free survival (PFS) [ Time Frame: time from randomization to a defined event. ] [ Designated as safety issue: No ]

time from randomization to one of the following events, whichever comes first:

Tumor progression at any time (progression of primary tumor or local lymph nodes, appearance of new lesions)

Recurrence at local, regional or distant site after surgery

Death from any cause

Secondary Outcome Measures:

Progression-free survival after surgery [ Time Frame: from date of surgery to an event as defined in PFS. ] [ Designated as safety issue: No ]

Adverse events according to CTCAE version 4.0 and major postoperative complications [ Time Frame: during treatment and follow-up period. ] [ Designated as safety issue: Yes ]

Pathological remission [ Time Frame: Assessed according to the tumor regression model of Mandard ] [ Designated as safety issue: No ]

Overall survival [ Time Frame: time from trial randomization to the date of death from any cause ] [ Designated as safety issue: No ]

Time to locoregional failure after R0 resection [ Time Frame: from date of surgery to date of first documented loco-regional failure ] [ Designated as safety issue: No ]

Time to systemic failure after R0 resection [ Time Frame: from date of surgery to date of first documented systemic failure ] [ Designated as safety issue: No ]

In-hospital mortality [ Time Frame: occurring after surgery but while the patient remains in hospital ] [ Designated as safety issue: No ]

Time to progression (TTP) [ Time Frame: Time to progression is defined as time from randomization to one of the following events, whichever comes first: - Tumor progression at any time. - Recurrence at local, regional or distant site after surgery. - Death due to tumor ] [ Designated as safety issue: No ]

All patients in the experimental arm will be given additional immunotherapy (cetuximab) during cycles 1 and 2, during RT and after surgery.

Biological: cetuximab

Loading dose 400 mg/m2 2h infusion Weekly: 250 mg/m2 1h infusion

Other Name: Erbitux

Drug: cisplatin

Cisplatin 75 mg/m2 1h infusion d1, 22

Cisplatin 25 mg/m2 1h infusion weekly x5

Drug: docetaxel

Docetaxel 75 mg/m2 1h infusion d1, 22

Docetaxel 20 mg/m2 1/2h infusion weekly x5

Other Name: Taxotere or generic product

Procedure: adjuvant therapy

During the adjuvant phase, all infusions, given every two weeks, will be at a dose of 500mg/m².

Procedure: neoadjuvant therapy

During the neoadjuvant phase, the first infusion of cetuximab should be at a dose of 400 mg/m² administered over a period of 2 hours and all subsequent infusions, given weekly, should be of 250 mg/m² over a period of 1 hour, unless any infusion related reaction was observed at a previous infusion. (The maximum infusion rate is 10 mg/min, corresponding to 2 mL/min ready-to-use solution.

Active Comparator: Without additional immunotherapy

Standard therapy without immunotherapy (cetuximab).

Drug: cisplatin

Cisplatin 75 mg/m2 1h infusion d1, 22

Cisplatin 25 mg/m2 1h infusion weekly x5

Drug: docetaxel

Docetaxel 75 mg/m2 1h infusion d1, 22

Docetaxel 20 mg/m2 1/2h infusion weekly x5

Other Name: Taxotere or generic product

Detailed Description:

OBJECTIVES:

Primary

To determine the efficacy of neoadjuvant radiochemotherapy comprising docetaxel, cisplatin, and radiotherapy in combination with cetuximab followed by surgery and adjuvant cetuximab versus neoadjuvant radiochemotherapy comprising docetaxel, cisplatin, and radiotherapy followed by surgery in patients with locally advanced esophageal carcinoma.

Secondary

To compare the toxicity of the two therapy arms.

To determine patterns of failure overall and with regard to histology.

To evaluate economic aspects in a subproject and to perform a radiotherapy quality assurance program.

Induction chemotherapy (docetaxel and cisplatin) and concurrent cetuximab Patients receive docetaxel IV over 1 hour and cisplatin IV over 1 hour on day 1 and cetuximab IV over 1-2 hours on day 1, 8, and 15. Treatment repeats every 21 days for 2 courses.

No T1, any N, M0; or T2, N0, M0; T4a (due to infiltration of the trachea-bronchial tree or organ involvement that cannot be operated on with curative intent [R0] as decided by a multidisciplinary team discussion); T4b; or distant metastasis (M1)

Type I or II disease according to the Siewert classification

Squamous cell carcinoma (including basaloid-squamous cell and adenosquamous carcinoma) or adenocarcinoma of the thoracic esophagus or the esophagogastric junction (from 5 cm below the entrance of the esophagus into the thorax to the gastric cardia)

Patients with obstructive tumors are eligible (obstructive tumors will be considered as locally advanced tumors)

No cervical esophageal carcinoma and tumors involving the first 5 cm of the thoracic esophagus

No airway infiltration in case of tumors at or above the tracheal bifurcation

No peritoneal carcinomatosis in case of adenocarcinomas infiltrating the gastric cardia (i.e., esophagogastric junction carcinoma Siewert type I or II)

PATIENT CHARACTERISTICS:

WHO performance status 0-1

Neutrophil count ≥ 1.5 x 10^9/L

Platelet count ≥ 100 x 10^9/L

Creatinine clearance > 60 mL/min

Bilirubin ≤ 1.0 times upper limit of normal (ULN)

Alkaline phosphatase ≤ 2.5 times ULN

AST ≤ 1.5 times ULN

INR normal

PTT ≤ 1.0 times ULN

Not pregnant or nursing

Negative pregnancy test

Fertile patients must use effective contraception during and for 12 months after completion of study therapy

FEV_1 ≥ 1.5 L OR ≥ 75% of the reference value

Must be compliant and geographically proximal for staging and follow-up

Considered operable (i.e., appropriate organ functions and ability to undergo general anesthesia)

No other malignancies within the past 5 years except nonmelanomatous skin cancer or adequately treated carcinoma in situ of the cervix

No severe or uncontrolled cardiovascular disease, including any of the following:

No serious underlying medical condition that, in the opinion of the investigator, could impair the ability of the patient to participate in the trial (e.g., uncontrolled diabetes mellitus or active autoimmune disease)

No preexisting peripheral neuropathy > grade 1

No definite contraindications for the use of corticosteroids and antihistamines as premedication

No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs

PRIOR CONCURRENT THERAPY:

No prior chemotherapy or radiotherapy to the chest

At least 30 days since prior treatment in another clinical trial

No concurrent drugs contraindicated for use with the trial drugs

No other concurrent anticancer treatments

No other concurrent experimental drugs or investigational treatments

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01107639